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D.X. Zhang
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-016 - BPI-7701, a Covalent Mutant-Selective EGFR Inhibitor, Inhibits the Growth of NSCLC Lines with EGFR Activating and T790M Resistance Mutations (ID 2708)
09:30 - 09:30 | Author(s): D.X. Zhang
- Abstract
Background:
First generation EGFR TKIs, erlotinib, gefitinib and icotinib, have shown excellent clinical efficacy in non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, patients eventually progress due to acquired resistance in the form of a T790M point mutation. This mutation occurs in about 50-60% of EGFR TKI treated patients. Second generation, irreversible EGFR TKIs, afatinib and dacomitinib, express even higher kinase potency in the activating mutation as well as potency against the acquired resistance mutation. Clinical efficacy of these TKIs is reduced due to the dose limiting toxicities of the drugs, attributed to wild type EGFR potency of the compounds. In order to improve clinical efficacy against the activating and double mutant EGFR tumor cells, it is important to build in selectivity against wild type EGFR to avoid dose-limiting toxicities. Here, we present BPI-7701, a novel EGFR inhibitor with high potency against the activating mutant EGFR and the T790M resistance mutation with good selectivity over wild type EGFR.
Methods:
BPI-7701 was evaluated in biochemical and in vitro assays against mutant EGFR (L858R, del ex19, del ex19/T790M) and WT EGFR. In vivo anti-tumor activity was evaluated in xenografts of HCC827 (del ex19) and H1975 (del ex19/T790M) NSCLC cells.
Results:
Biochemical assays showed that BPI-7701 inhibited del ex19 and L858R mutant EGFR, as well as the T790M resistance mutation of EGFR at IC~50 ~values lower than that of WT EGFR, showing an ~100-fold difference in activity. BPI-7701 showed growth inhibition of PC-9 (del ex19), HCC827 (L858R) and H1975 (del ex19/T790M) cells in vitro, with IC~50~ values of 11-160 nM. BPI-7701 showed an IC~50~ value of 1.25 μM against A431, wild type EGFR epithelial cells. In vivo, BPI-7701 showed greater than 90% inhibition of pEGFR at tested doses as low as 6.25 mpk in nude mice. pEGFR inhibition was dose-dependent and was maintained over the course of 24 hours. In mouse xenograft studies, BPI-7701 induced complete tumor regression in H1975 (del ex19/T790M) and HCC827 (L858R) NSCLC cell lines after 14-day repeat dose treatment. In an H1975 xenograft model, complete tumor regression occurred after 6 days of BPI-7701 treatment (14-day regimen), with 80% of mice remaining tumor-free 35 days after the completion of BPI-7701 dosing.
Conclusion:
BPI-7701 inhibits the growth of NSCLC cells with EGFR mutations and T790M resistance mutation, both in vitro and in vivo. BPI-7701 may be an excellent option for NSCLC patients with activating EGFR mutations. Clinical trials are planned to begin Q2 2016 in Asia.
